A continuation of our current research on the intrinsic innervation (II) of the heart is the overall objective of this proposal. The specific aspects of the problem to be investigated are: 1) Assessment of the effects of II stimulation on electrical conduction in the atrium; 2) Functional capabilities of proposed chromaffin cell (CC) component of the II; 3) The existence and nature of II tonic activity in normal and neurally-deprived hearts; 4) The pattern of distribution of the right and left vagi to the intrinsic parasympathic-neurones (IPN) of the four cardiac chambers. Various chronic animal preparations will be employed including: bilateral cervicothoracic sympathectomies, 6-hydroxydopamine pre-treated animals, unilateral vagotomies and animals with total extrinsic cardiac denervation. Acute preparations will all be done on total cardiopulmonary bypass. In some preparations, multiple atrial electrograms in addition to a His bundle electrogram will be recorded in order to examine atrial electrical conduction. In other preparations, isovolumic pressures will be recorded from the four cardiac chambers. The II will be activated using intracoronary injections of nicotine (NIC) while the responses of the effector cells to muscarinic stimulation will be tested with acetylcholine (ACh). II activation will be verified by the blockade of the NIC responses with intracoronary tetrodotoxin (TTX). NIC injections will be used in an attempt to activate CC after muscarinic blockade in animals sympathectomized chemically or surgically. The tonic activity of the II will be examined in normal and denervated animals by observing the changes in contractility or electrical activity in response to atropine injection. These responses will be observed after elimination of II activity with TTX or after elimination of afferent input in extrinsically denervated or sympathectomized animals. Finally, the inotropic responses of each chamber to various doses of NIC will be measured in animals previously subjected to either right or left cervical vagotomy. The chambers deprived of vagal preganglionic fibers should demonstrate an increased sensitivity to NIC because of the denervation of the IPN. In this way, the distribution of the right and left vagi to the II of the atria and ventricles may be determined.